CL2020001349A1 - Compounds, composition and use of the same as modulators of the expression of pcsk9. (divisional request 201902574) - Google Patents

Compounds, composition and use of the same as modulators of the expression of pcsk9. (divisional request 201902574)

Info

Publication number
CL2020001349A1
CL2020001349A1 CL2020001349A CL2020001349A CL2020001349A1 CL 2020001349 A1 CL2020001349 A1 CL 2020001349A1 CL 2020001349 A CL2020001349 A CL 2020001349A CL 2020001349 A CL2020001349 A CL 2020001349A CL 2020001349 A1 CL2020001349 A1 CL 2020001349A1
Authority
CL
Chile
Prior art keywords
pcsk9
compounds
expression
modulators
composition
Prior art date
Application number
CL2020001349A
Other languages
Spanish (es)
Inventor
Susan M Freier
Eric E Swayze
Huynh-Hoa Bui
Original Assignee
Ionis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ionis Pharmaceuticals Inc filed Critical Ionis Pharmaceuticals Inc
Publication of CL2020001349A1 publication Critical patent/CL2020001349A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21061—Kexin (3.4.21.61), i.e. proprotein convertase subtilisin/kexin type 9

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Las presentes realizaciones proporcionan métodos, compuestos y composiciones para inhibir la expresión de PCSK9, lo que puede ser útil para tratar, prevenir o mejorar una enfermedad asociada con PCSK9, tal como hipercolesterolemia, dislipidemia o dislipidemia mixta.The present embodiments provide methods, compounds, and compositions for inhibiting PCSK9 expression, which may be useful in treating, preventing, or ameliorating a disease associated with PCSK9, such as hypercholesterolemia, dyslipidemia, or mixed dyslipidemia.

CL2020001349A 2017-03-24 2020-05-22 Compounds, composition and use of the same as modulators of the expression of pcsk9. (divisional request 201902574) CL2020001349A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201762476051P 2017-03-24 2017-03-24

Publications (1)

Publication Number Publication Date
CL2020001349A1 true CL2020001349A1 (en) 2020-10-30

Family

ID=63584761

Family Applications (2)

Application Number Title Priority Date Filing Date
CL2019002574A CL2019002574A1 (en) 2017-03-24 2019-09-10 Modulators of pcsk9 expression.
CL2020001349A CL2020001349A1 (en) 2017-03-24 2020-05-22 Compounds, composition and use of the same as modulators of the expression of pcsk9. (divisional request 201902574)

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CL2019002574A CL2019002574A1 (en) 2017-03-24 2019-09-10 Modulators of pcsk9 expression.

Country Status (27)

Country Link
US (4) US10517953B2 (en)
EP (2) EP3601569B1 (en)
JP (3) JP7022143B2 (en)
KR (1) KR102645714B1 (en)
CN (1) CN110446784A (en)
AR (1) AR113214A1 (en)
AU (2) AU2018237306B2 (en)
BR (1) BR112019015041A2 (en)
CA (1) CA3056129A1 (en)
CL (2) CL2019002574A1 (en)
CO (1) CO2019011265A2 (en)
CR (1) CR20190471A (en)
DO (1) DOP2019000232A (en)
EA (1) EA201992170A1 (en)
EC (1) ECSP19072372A (en)
IL (2) IL269273A (en)
JO (1) JOP20190215A1 (en)
MX (1) MX2019010699A (en)
MY (1) MY194227A (en)
NI (1) NI201900096A (en)
NZ (1) NZ758177A (en)
PE (1) PE20191484A1 (en)
PH (1) PH12019502174A1 (en)
SG (1) SG11201908393YA (en)
TW (2) TW202325310A (en)
UA (1) UA127390C2 (en)
WO (1) WO2018175839A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11273222B2 (en) * 2017-05-26 2022-03-15 National Cerebral And Cardiovascular Center Antisense nucleic acid targeting PCSK9
KR20230069186A (en) * 2020-09-17 2023-05-18 아스트라제네카 아베 Pharmaceutical composition comprising an antisense oligonucleotide for oral administration
EP4213860A1 (en) * 2020-09-17 2023-07-26 Astrazeneca AB Pcsk9 inhibitors and methods of treatment using same
WO2022089486A1 (en) * 2020-10-28 2022-05-05 江苏柯菲平医药股份有限公司 Sirna for inhibiting pcsk9 gene expression and modifier thereof and use thereof
WO2022226217A1 (en) 2021-04-22 2022-10-27 Civi Biopharma, Inc. Oral delivery of oligonucleotides

Family Cites Families (143)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
FR2575751B1 (en) 1985-01-08 1987-04-03 Pasteur Institut NOVEL ADENOSINE DERIVATIVE NUCLEOSIDES, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS
US4751219A (en) 1985-02-05 1988-06-14 Nederlandse Centrale Organisatie Voor Toegepast-Natuur-Wetenschappelijk Onderzoek Synthetic glycolipides, a process for the preparation thereof and several uses for these synthetic glycolipides
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
ATE113059T1 (en) 1987-06-24 1994-11-15 Florey Howard Inst NUCLEOSIDE DERIVATIVES.
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5859221A (en) 1990-01-11 1999-01-12 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US6005087A (en) 1995-06-06 1999-12-21 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
CA2088258C (en) 1990-07-27 2004-09-14 Phillip Dan Cook Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
TW393513B (en) 1991-11-26 2000-06-11 Isis Pharmaceuticals Inc Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
EP1256589A3 (en) 1991-11-26 2003-09-17 Isis Pharmaceuticals, Inc. Oligomers containing modified pyrimidines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US6172045B1 (en) 1994-12-07 2001-01-09 Neorx Corporation Cluster clearing agents
US6908903B1 (en) 1994-12-07 2005-06-21 Aletheon Pharmaceuticals, Inc. Cluster clearing agents
US20030119724A1 (en) 1995-11-22 2003-06-26 Ts`O Paul O.P. Ligands to enhance cellular uptake of biomolecules
TW520293B (en) 1995-11-22 2003-02-11 Univ Johns Hopkins Med Delivery system to enhance cellular uptake of biomolecules
CN1231675A (en) 1996-09-26 1999-10-13 味之素株式会社 Modified physiologically active proteins and medicinal compositions containing the same
USRE44779E1 (en) 1997-03-07 2014-02-25 Santaris Pharma A/S Bicyclonucleoside and oligonucleotide analogues
JP3756313B2 (en) 1997-03-07 2006-03-15 武 今西 Novel bicyclonucleosides and oligonucleotide analogues
US6770748B2 (en) 1997-03-07 2004-08-03 Takeshi Imanishi Bicyclonucleoside and oligonucleotide analogue
US7572582B2 (en) 1997-09-12 2009-08-11 Exiqon A/S Oligonucleotide analogues
CA2303299C (en) 1997-09-12 2016-02-23 Exiqon A/S Oligonucleotide analogues
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
BR0009884A (en) 1999-04-21 2002-01-08 American Home Prod Processes and compositions for inhibiting the function of polynucleotide sequences
CA2372085C (en) 1999-05-04 2009-10-27 Exiqon A/S L-ribo-lna analogues
US6525191B1 (en) 1999-05-11 2003-02-25 Kanda S. Ramasamy Conformationally constrained L-nucleosides
US6383812B1 (en) 1999-05-28 2002-05-07 Academia Sinica Anti liver disease drug R-YEEE and method of synthesizing branched galactose-terminal glycoproteins
US8541548B2 (en) 1999-06-07 2013-09-24 Arrowhead Madison Inc. Compounds and methods for reversible modification of biologically active molecules
US20080281041A1 (en) 1999-06-07 2008-11-13 Rozema David B Reversibly Masked Polymers
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
CN100406065C (en) 2000-12-01 2008-07-30 细胞工厂治疗公司 Conjugates of glycosylated/galactosylated peptide, bifunctional linker and nucleotidic monomers/polymers, and related compositions and method of use
WO2002087541A1 (en) 2001-04-30 2002-11-07 Protiva Biotherapeutics Inc. Lipid-based formulations for gene transfer
US20070173473A1 (en) * 2001-05-18 2007-07-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of proprotein convertase subtilisin Kexin 9 (PCSK9) gene expression using short interfering nucleic acid (siNA)
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
US20100240730A1 (en) 2002-02-20 2010-09-23 Merck Sharp And Dohme Corp. RNA Interference Mediated Inhibition of Gene Expression Using Chemically Modified Short Interfering Nucleic Acid (siNA)
WO2004024757A2 (en) 2002-09-11 2004-03-25 Santaris Pharma A/S Modified pna molecules
US7696345B2 (en) 2002-11-05 2010-04-13 Isis Pharmaceuticals, Inc. Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
WO2004044139A2 (en) 2002-11-05 2004-05-27 Isis Parmaceuticals, Inc. Modified oligonucleotides for use in rna interference
US6673661B1 (en) 2002-12-20 2004-01-06 Taiwan Semiconductor Manufacturing Co., Ltd. Self-aligned method for forming dual gate thin film transistor (TFT) device
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7851615B2 (en) 2003-04-17 2010-12-14 Alnylam Pharmaceuticals, Inc. Lipophilic conjugated iRNA agents
EP2664672A1 (en) 2003-04-17 2013-11-20 Alnylam Pharmaceuticals Inc. Modified iRNA agents
WO2004101619A1 (en) 2003-05-15 2004-11-25 Shionogi Co., Ltd. Rational design and synthesis of functional glycopeptide
WO2004106356A1 (en) 2003-05-27 2004-12-09 Syddansk Universitet Functionalized nucleotide derivatives
JP4731324B2 (en) 2003-08-28 2011-07-20 武 今西 N-O bond cross-linked novel artificial nucleic acid
JP5379347B2 (en) 2003-09-18 2013-12-25 アイシス ファーマシューティカルズ， インコーポレーテッド 4'-thionucleosides and oligomeric compounds
US7582744B2 (en) 2004-08-10 2009-09-01 Alnylam Pharmaceuticals, Inc. Chemically modified oligonucleotides
WO2006031461A2 (en) 2004-09-09 2006-03-23 Isis Pharmaceuticals, Inc. Pyrrolidinyl groups for attaching conjugates to oligomeric compounds
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
EP1841867A1 (en) 2005-01-24 2007-10-10 Avaris AB COMPLEX CONTAINING SiRNA, ShRNA OR ANTISENSE MOLECULE AND FUNCTIONAL ENTITY, FOR IMPROVED SPECIFICITY AND DELIVERY
PL1934388T3 (en) * 2005-10-04 2013-04-30 Alchemia Ltd Method of drug design
JP5342881B2 (en) 2006-01-27 2013-11-13 アイシス ファーマシューティカルズ， インコーポレーテッド 6-modified bicyclic nucleic acid analogues
US7569686B1 (en) 2006-01-27 2009-08-04 Isis Pharmaceuticals, Inc. Compounds and methods for synthesis of bicyclic nucleic acid analogs
DK2015758T3 (en) 2006-05-05 2014-06-23 Isis Pharmaceuticals Inc RELATIONS AND PROCEDURES FOR MODULATING APOB EXPRESSION
US7547684B2 (en) 2006-05-11 2009-06-16 Isis Pharmaceuticals, Inc. 5′-modified bicyclic nucleic acid analogs
US7666854B2 (en) 2006-05-11 2010-02-23 Isis Pharmaceuticals, Inc. Bis-modified bicyclic nucleic acid analogs
ES2392478T3 (en) * 2006-05-11 2012-12-11 Alnylam Pharmaceuticals Inc. Compositions and methods to inhibit PCSK9 gene expression
US8658211B2 (en) 2006-08-18 2014-02-25 Arrowhead Madison Inc. Polyconjugates for in vivo delivery of polynucleotides
AU2007285782B2 (en) 2006-08-18 2010-06-24 Arrowhead Research Corporation Polyconjugates for in vivo delivery of polynucleotides
ES2377327T5 (en) 2006-10-18 2020-04-28 Ionis Pharmaceuticals Inc Antisense compounds
TW200838551A (en) 2006-11-27 2008-10-01 Isis Pharmaceuticals Inc Methods for treating hypercholesterolemia
EP2125852B1 (en) 2007-02-15 2016-04-06 Ionis Pharmaceuticals, Inc. 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom
EP2609934A1 (en) 2007-02-16 2013-07-03 KTB Tumorforschungsgesellschaft mbH Receptor And Antigen Targeted Prodrug
WO2008109369A2 (en) * 2007-03-02 2008-09-12 Mdrna, Inc. Nucleic acid compounds for inhibiting tnf gene expression and uses thereof
US8877917B2 (en) 2007-04-23 2014-11-04 Alnylam Pharmaceuticals, Inc. Glycoconjugates of RNA interference agents
US8278425B2 (en) 2007-05-30 2012-10-02 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
WO2008154401A2 (en) 2007-06-08 2008-12-18 Isis Pharmaceuticals, Inc. Carbocyclic bicyclic nucleic acid analogs
AU2008272918B2 (en) 2007-07-05 2012-09-13 Isis Pharmaceuticals, Inc. 6-disubstituted bicyclic nucleic acid analogs
US8088904B2 (en) 2007-08-15 2012-01-03 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8546556B2 (en) 2007-11-21 2013-10-01 Isis Pharmaceuticals, Inc Carbocyclic alpha-L-bicyclic nucleic acid analogs
AU2008333811B2 (en) 2007-12-04 2014-05-01 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
AU2009241591A1 (en) 2008-01-31 2009-11-05 Alnylam Pharmaceuticals, Inc. Optimized methods for delivery of DSRNA targeting the PCSK9 gene
EP2265627A2 (en) 2008-02-07 2010-12-29 Isis Pharmaceuticals, Inc. Bicyclic cyclohexitol nucleic acid analogs
WO2009114475A2 (en) * 2008-03-09 2009-09-17 Intradigm Corporation Compositions comprising human pcsk9 and apolipoprotein b sirna and methods of use
US20110130440A1 (en) 2008-03-26 2011-06-02 Alnylam Pharmaceuticals, Inc. Non-natural ribonucleotides, and methods of use thereof
US8575123B2 (en) 2008-04-11 2013-11-05 Tekmira Pharmaceuticals Corporation Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
WO2009148605A2 (en) * 2008-06-04 2009-12-10 Isis Pharmaceuticals, Inc. Methods for treating hypercholesterolemia
EP2342616A2 (en) 2008-09-23 2011-07-13 Alnylam Pharmaceuticals Inc. Chemical modifications of monomers and oligonucleotides with cycloaddition
DK2356129T3 (en) 2008-09-24 2013-05-13 Isis Pharmaceuticals Inc Substituted alpha-L bicyclic nucleosides
KR20210158864A (en) 2008-11-10 2021-12-31 알닐람 파마슈티칼스 인코포레이티드 Novel lipids and compositions for the delivery of therapeutics
AU2010208035B2 (en) 2009-01-29 2016-06-23 Arbutus Biopharma Corporation Improved lipid formulation for the delivery of nucleic acids
EP3097908A1 (en) 2009-05-05 2016-11-30 Arbutus Biopharma Corporation Lipid compositions
PT3431076T (en) 2009-06-10 2021-10-26 Arbutus Biopharma Corp Improved lipid formulation
MX2011013421A (en) 2009-06-15 2012-03-16 Alnylam Pharmaceuticals Inc Lipid formulated dsrna targeting the pcsk9 gene.
WO2011017521A2 (en) 2009-08-06 2011-02-10 Isis Pharmaceuticals, Inc. Bicyclic cyclohexose nucleic acid analogs
US8552163B2 (en) 2009-09-25 2013-10-08 Johns Hopkins University Liver-targeting agents and their synthesis
TWI391144B (en) 2009-10-26 2013-04-01 Iner Aec Executive Yuan A quantification method for remaining liver function with a novel liver receptor imaging agent
TWI388338B (en) 2009-10-26 2013-03-11 Iner Aec Executive Yuan Method of radiolabelling multivalent glycoside for using as hepatic receptor imaging agent
WO2011072290A2 (en) 2009-12-11 2011-06-16 The Regents Of The University Of Michigan Targeted dendrimer-drug conjugates
US9198972B2 (en) 2010-01-28 2015-12-01 Alnylam Pharmaceuticals, Inc. Monomers and oligonucleotides comprising cycloaddition adduct(s)
AP3284A (en) 2010-02-24 2015-05-31 Arrowhead Res Corp Compositions for targeted delivery of SIRNA
US20130109817A1 (en) 2010-03-26 2013-05-02 Mersana Therapeutics, Inc. Modified Polymers for Delivery of Polynucleotides, Method of Manufacture, and Methods of Use Thereof
EP2553019A1 (en) 2010-03-26 2013-02-06 Mersana Therapeutics, Inc. Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof
US9102938B2 (en) 2010-04-01 2015-08-11 Alnylam Pharmaceuticals, Inc. 2′ and 5′ modified monomers and oligonucleotides
US10913767B2 (en) 2010-04-22 2021-02-09 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising acyclic and abasic nucleosides and analogs
WO2011163121A1 (en) 2010-06-21 2011-12-29 Alnylam Pharmaceuticals, Inc. Multifunctional copolymers for nucleic acid delivery
US9290760B2 (en) 2010-09-15 2016-03-22 Alnylam Pharmaceuticals, Inc. Modified iRNA agents
EP2640400A4 (en) 2010-11-19 2016-01-20 Sirna Therapeutics Inc Poly(amide) polymers for the delivery of oligonucleotides
US8501930B2 (en) 2010-12-17 2013-08-06 Arrowhead Madison Inc. Peptide-based in vivo siRNA delivery system
CN103492568B (en) 2010-12-17 2017-04-12 箭头研究公司 Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA
CA3131967A1 (en) 2010-12-29 2012-07-05 F. Hoffman-La Roche Ag Small molecule conjugates for intracellular delivery of nucleic acids
EP3067421B1 (en) 2011-02-08 2018-10-10 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
MX344807B (en) 2011-06-21 2017-01-09 Alnylam Pharmaceuticals Inc Compositions and methods for inhibition of expression of apolipoprotein c-iii (apoc3) genes.
CA2842039A1 (en) 2011-08-26 2013-03-07 Arrowhead Research Corporation Poly(vinyl ester) polymers for in vivo nucleic acid delivery
US10023861B2 (en) 2011-08-29 2018-07-17 Ionis Pharmaceuticals, Inc. Oligomer-conjugate complexes and their use
US9399775B2 (en) 2011-11-18 2016-07-26 Alnylam Pharmaceuticals, Inc. RNAi agents, compositions and methods of use thereof for treating transthyretin (TTR) associated diseases
US9914922B2 (en) 2012-04-20 2018-03-13 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
EP3919620A1 (en) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Short interfering nucleic acid (sina) compositions
TW201808342A (en) 2012-05-02 2018-03-16 喜納製藥公司 Novel tetraGALNAC containing conjugates and methods for delivery of oligonucleotides
WO2014059353A2 (en) 2012-10-11 2014-04-17 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleosides and uses thereof
RS56783B9 (en) * 2012-12-05 2021-12-31 Alnylam Pharmaceuticals Inc Pcsk9 irna compositions and methods of use thereof
US9450467B2 (en) 2013-03-14 2016-09-20 Summin Holding Company, Llc Submersible pump
CA2921514C (en) * 2013-05-01 2023-10-24 Ionis Pharmaceuticals, Inc. Compositions and methods for modulating apolipoprotein c-iii expression
CN112263682A (en) * 2013-06-27 2021-01-26 罗氏创新中心哥本哈根有限公司 Antisense oligomers and conjugates targeting PCSK9
JP2017501684A (en) * 2013-11-14 2017-01-19 ロシュ・イノベーション・センター・コペンハーゲン・アクティーゼルスカブＲｏｃｈｅ Ｉｎｎｏｖａｔｉｏｎ Ｃｅｎｔｅｒ Ｃｏｐｅｎｈａｇｅｎ Ａ／Ｓ APOB antisense conjugate compound
WO2015106128A2 (en) 2014-01-09 2015-07-16 Alnylam Pharmaceuticals, Inc. MODIFIED RNAi AGENTS
PT3137596T (en) * 2014-05-01 2019-09-27 Ionis Pharmaceuticals Inc Compositions and methods for modulating complement factor b expression
US20170145424A1 (en) * 2014-06-06 2017-05-25 Ionis Pharmaceuticals, Inc. Compositions and methods for enhanced intestinal absorption of conjugated oligomeric compounds
WO2017191503A1 (en) * 2016-05-05 2017-11-09 Crispr Therapeutics Ag Materials and methods for treatment of hemoglobinopathies
JOP20190112A1 (en) 2016-11-14 2019-05-14 Amgen Inc Combined therapies for atherosclerosis, including atherosclerotic cardiovascular disease
CA3053709A1 (en) * 2017-02-22 2018-08-30 Crispr Therapeutics Ag Compositions and methods for treatment of proprotein convertase subtilisin/kexin type 9 (pcsk9)-related disorders
US11273222B2 (en) 2017-05-26 2022-03-15 National Cerebral And Cardiovascular Center Antisense nucleic acid targeting PCSK9
EP3630199A4 (en) 2017-06-02 2021-11-10 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof

Also Published As

Publication number Publication date
EP3601569A4 (en) 2021-01-13
US11633483B2 (en) 2023-04-25
CL2019002574A1 (en) 2020-01-03
WO2018175839A1 (en) 2018-09-27
BR112019015041A2 (en) 2020-03-10
AR113214A1 (en) 2020-02-19
TWI794217B (en) 2023-03-01
EP3601569A1 (en) 2020-02-05
US20210077630A1 (en) 2021-03-18
IL304618A (en) 2023-09-01
PE20191484A1 (en) 2019-10-18
JP7022143B2 (en) 2022-02-17
JP2023109989A (en) 2023-08-08
JP2022046621A (en) 2022-03-23
EP3601569B1 (en) 2023-09-27
AU2018237306B2 (en) 2021-12-09
CA3056129A1 (en) 2018-09-27
US20230321255A1 (en) 2023-10-12
KR102645714B1 (en) 2024-03-12
MX2019010699A (en) 2020-01-27
NI201900096A (en) 2020-07-22
JP7289347B2 (en) 2023-06-09
US20180311365A1 (en) 2018-11-01
US10517953B2 (en) 2019-12-31
US11000595B2 (en) 2021-05-11
PH12019502174A1 (en) 2020-03-16
AU2022201092A1 (en) 2022-03-10
MY194227A (en) 2022-11-23
CN110446784A (en) 2019-11-12
CR20190471A (en) 2019-12-13
JP2020511155A (en) 2020-04-16
US20200197525A1 (en) 2020-06-25
EP4309732A2 (en) 2024-01-24
DOP2019000232A (en) 2019-09-30
SG11201908393YA (en) 2019-10-30
ECSP19072372A (en) 2019-12-27
AU2018237306A1 (en) 2019-10-31
EA201992170A1 (en) 2020-03-16
CO2019011265A2 (en) 2019-10-31
UA127390C2 (en) 2023-08-09
JOP20190215A1 (en) 2019-09-19
TW201840847A (en) 2018-11-16
NZ758177A (en) 2022-11-25
KR20190131532A (en) 2019-11-26
IL269273A (en) 2019-11-28
TW202325310A (en) 2023-07-01

Similar Documents

Publication Publication Date Title
CL2020001349A1 (en) Compounds, composition and use of the same as modulators of the expression of pcsk9. (divisional request 201902574)
CL2021003477A1 (en) 2,3-dihydroquinazoline compounds as nav1 .8 inhibitors
UY38403A (en) ALPHA-1 ANTITRYPSIN MODULATORS
CL2020000075A1 (en) Carboxamides as modulators of sodium channels.
CO2022003782A2 (en) Kras g12d inhibitors
CO2021004141A2 (en) Modulators of pnpla3 expression
CL2020003257A1 (en) Pcsk9 antagonist compounds.
CO2018003168A2 (en) Kras expression modulators
UY37952A (en) FORMULATIONS OF AN INHIBITOR OF THE QUINASA TRK MACROCYCLIC
CL2008000202A1 (en) Compounds derived from n-aryl-acetamide, trpv1 antagonist, pharmaceutical composition that comprises them, useful in the treatment of pain.
ECSP20082339A (en) MODULATORS OF APOL1 EXPRESSION
CL2012002887A1 (en) Pharmaceutical combination comprising compounds derived from substituted 2,3-dihydroimidazo [1,2-c] quinazoline, compounds derived from n- (2-arylamino) arylsulfonamide and optionally other additional pharmaceutical agents; pharmaceutical kit; treatment method; and its use for the treatment or prophylaxis of cancer.
SV2017005466A (en) PIRAZOLPIRIDINAMINS AS INHIBITORS OF MKNK1 AND MKNK2
CL2017002214A1 (en) Combination formulation of tesofensin and beta blocker
CU20200008A7 (en) SUBSTITUTE DIHYDROOXADIAZINONE COMPOUNDS USEFUL IN THE TREATMENT OF HYPERPROLIFERATIVE DISEASES, METHODS FOR PREPARING SUCH COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CO2022006466A2 (en) Allosteric egfr inhibitors and methods of use thereof
PE20210109A1 (en) IRF4 EXPRESSION MODULATORS
CO2022000270A2 (en) enzyme inhibitors
CO2022000266A2 (en) enzyme inhibitors
CO2021007006A2 (en) Modulators of irf5 expression
CO2020008769A2 (en) Modulators of the dnm2 expression
CO2020003134A2 (en) Modulators of enac expression
BR112019002213A2 (en) compositions and their use to treat or prevent rosacea
CL2022001015A1 (en) Use of imidazopyrimidine or imidazotriazine compounds for prevention, relief or treatment of cognitive disorders.
ECSP21042779A (en) MODULATORS OF IRF5 EXPRESSION